Salts of furan carboxylic acids with thiamine and its salts



United States Patent me Patented Mar. 11, 1969 1 2 3 432 504 Other objects of the present invention and advantageous SALTS 0F FURAN CARfiOXYLIC ACIDS WITH features thereof will become apparent as the description THIAMINE AND ITS SALTS Prmed? Wolfgang Goetze-Claren, New York, N.Y, In principle the present mventron relates to new and (Via Mangili 30, Rome, Italy) 5 Valuable thiamine compounds with furan carboxylic acids. N0 Drawing. Filed June 28, 1966, Ser. No. 561,065 Such compounds correspond to Formula I: US. Cl. 260256.6 9 Claims Int. Cl. 'C07d 99/12; A61k 15/12 HaC(|3 (IJNH2.Y CH fi-CHz-CHaOR 10 /CCH-I: I CH: ABSTRACT OF THE DISCLOSURE o J There are disclosed the salts of thiamine, its salts, its 1'1 X 1 O-phosphorus acid esters, and their salts with 2-furan carboxylic acid and 2,5-furan dicarboxylic acid. Also are disclosed pharmaceutical compositions and methods of using X 18 the anion of Z-furan carboxylic acid, 2,5-furan d1- these compounds in treating vitamin B deficiencies. carboifyhc acld, a Pharmaceutlcally acceptabl? organic or organic acid such as hydrochloric acid, c1tr1c acid, phosphoric acid, naphthalene-1,5-disulfonic acid,

In said formula:

The present invention relates to salts and derivatives of a Others; furan carboxylic acids and more particularly to salts and 20 Y 13 carbolfyllc acld, dlcalfboxyllc aclfl, derivatives of furan carboxylic acids with thiamine and 1 pharmaceutlcally q p i lllofgalll? 9 g its Salts and derivatives, and to a process f making and acid such as hydrochloric acld, phosphoric acid, and using such salts and derivatives. others;

The watepsoluble Vitamin B1 (thiamine) is widely R is hydrogen or an ester-forming phosphoric acid or tritributed in natural foodstuffs. However, it is lost to a Phosphorlc acld resldue of the formula s 2 large extent On cooking food whereby it is discarded in PO3H PO3H PO3H2 3 3 W the water used for boiling. It is also lost on milling wheat. y least one of sald f f X and It is present in whole-grain, legumes, beef, pork, liver, nuts nved f z'furan carboxyhc and or 254mm meat and yeast as well as in eggs, fish, and other vegetable food boxyhc ac1dmaterial. The daily intake, however, is usually too small Thiamine compounds as they are provided according thflt most bjlsllless y P p S11E61 a marked to the present invention thus correspond to the following vitamin B defic1ency chronlcally. fo l It 18 object of the p e mvergtwn pr e (a) The thiamine compound with 2-furan carboxylic and valuable salts of thlamine and 1ts derrvatlves which i have an increased and prolonged vitamin B activity. N S

Another object of the present invention is to provide a new and valuable thiamine ester of improved therapeutic HO 04732-932011 activi y. CH2 -o113 GHCH A further object of the present invention is to provide f 3 [l C 00 a new and valuable thiamine phosphoric acid ester compound of improved therapeutic activity. H O H A further object of the present invention is to provide and its amine salt with 2-furan carboxylic acid or other a simple and effective process of making such new and acids. valuable thiamine salts and compounds. (b) The thiamine compound with 2,5-furan dicarbox- Still another object of the present invention is to provide ylic acid Ego-(l3 3NH2 HO C-CHz-CHzOH C-CH N CCH oil-0H II II H0OOO\ o-o00 H 0 III a pharmaceutical composition containing the aforesaid thi- (c) The salts of thiamine phosphoric acid esters or thiamine salts and derivatives. amine triphosphoric acid ester with Z-furan carboxylic Another object of the present invention is to provide acid or 2,5-furan carboxylic acid a method of using such compositions in therapy.

i HaC-(fi \CNH2 HC o-oHz-omo-P-oH -CH2- C-CHa HCCH l5 ll 0 Z COO' 1!! 0 IV 0H OH OH [mo-( f ('3NHz no o-oH2-omo r' *-0-%-o-r -o11 l N C-0H1N CHa 0 d o CHCH lg H zooo0- H 0 V wherein Z is hydrogen or the carboxyl group.

The compounds of Formulas II and III are prepared, for instance, by removing all chloride ions from thiamine chloride hydrochloride by treatment with alkali and reacting the resulting free thiamine base with a stoichiometric amount of 2,5-ifuran dicarboxylic acid and isolating the resulting salt from the reaction mixture.

Example 7 The Zafuran carboxylic acid salt of cocarboxylase, i.e.

amount of 2-furan carboxlic acid or 2,5-furan dicarboxthiamine ipyrophosphoric acid ester of Formula V1 is ylic acid. obtained by proceeding as described in Example 1.

A r r Ha -(I? ONHi HO (|TCHzCHzO1"Ofi-OH N CCHzN-C-CH o CHCH I ll 0 CH 0-000- II H 0 vi The compounds of Formulas -IV and V are produced, E a l 8 for lpstance from-the thlrfimme phosphonc acid estar The 2,5-furan dicarboxylic acid salt of cocarboxylasc, chloride hydrochlorides by ion exchange.

The new com ound and es eciau the salts of Pop i.e. thiamine pyrophosphoric acid ester 18 obtained in a mulas II and IHPhave sproved apvalueyas appearing tonic 20 similar manner is described in Example 2 by using 2,5- to overcome loss in appetite, low gastric acid, atony of furan dlcarboxyhc acid as the one reactant the stomach and intestines, constipation, and the tendency Example 9 towards colitis. They are also useful to ameliorate the The 2 furan carboxylic acid salt of thiamine triphos symptoms of cardio-vascular disturbances in all cases of horic acid ter of Formula H myocardial infraction and are helpful in degenerative p es v diseases, neurodermatitis, diphtheria, neuritis, and other /N 0H gszifgigleydiziegiycourse, also used in the treatment fi HO I, fi I I,

1 The new thiamine salts and compounds can be added l 2- O 0 to food, for instance, for enriching flour mixes. They C can also be employed as addition to animal feed.

The following examples serve to illustrate the present VII invention without however limitin the same thereto.

g wherein Y is Z- furan carboxylic acid obtained by add- Example 1 ing the stoichiometric amount of Z-furan carboxylic acid 33 7 g of thiamine chloride hydrochloride are to an aqueous solution of thiamine triphosphoric acid ester. solved in 200 cc. of water and 8 g. of sodium hydroxide The free amino group in the pyrimidine moiety of the ig igg fi g gg gj ig iisgyi gig g 2 822 40 new salts may also be converted into the acid addition f 1 reci itate of the carbox salt group whereby either a pharmaceutically acceptable g g i f i Z g z vghich is filtered off by suctizm inorganic or organic acid or an additional mole of Z-furan i i f at n. It is also possible to dilute the. reaction mixture with ?gg i g igfi z gj gzii g s lg g gg hi and g fi p g ifi i il Sal} 5 3 r its phosphoric acid esters can be administered orally and o i E i g 3 i g g parenterally. Compositions containing said salts as used 3 ou S 3 tr urgent in therapy comprise, for instance, tablets, pills, dragees, 15 so u lon can u e 1e 6 lozenges, and the like shaped preparations to be admin- Example 2 istered orally. The salts may also be administered in powder form, preferably inclosed in gelatin or the like cap The procedure is the same as described hereinabove sules. Oral administration in liquid form, such as in the whereby 8- 0f f fl d are used form of solutions, emulsions, suspensions, sirups, and the in place of the Z-furan carboxylic acid. like is also possible. Such solid and liquid preparations are E 1 3 produced in a manner known to the art of compounding Xamp e and processing pharmaceutical products whereby the con- The Z-furan carbox lic acid salt of thiamine phosphoric ventional diluting, binding, and/or expanding agents, lubriy I p u 0 c a acid ester is obtained by reacting thiamine phosphoric cants, and/or other excipients, such as lactose, cane sugar, acid ester chloride hydrochloride as described above. dextrins, starch, talc, kaolin, magnesium hydroxide, mag- 1 nesium carbonate, pectin, gelatin, agar, bentonite, stearic ExamPle 4 acid, magnesium stearate, and others may be employed. The 2-furan carboxylic acid salt of thiamine triphos- Of course, many changes and variations in therephoric acid is obtained by reacting thiamine triphosphoric actants, the reaction conditions, temperature, duration, acid ester with Z-furan carboxylic acid. n the solvents used, in the methods of isolating and purifying the reaction products, in the preparation of pharma- Ple 5 ceutical compositions, in their use in thera y, and the like b dbth killd'th d ii tinaccor ance wit The Z-furan carboxylic acid salt of thiamine phosphoric may F 3 e y 056 m 6 acid ester chloride is obtained by adding to the thiamine g lzrmclples Set forth and m the dams annexed phosphoric acid ester chloride the equimolecular amount i g of 2furan carboxylic acid and isolating the resulting salt from the reaction mixture. 1. A thiamine compound of the formula 8 Example 6 mo-o C-NHz-Y oh C--CH2CH1OR The 2,5-furan dicarboxylic acid salt of thiamine phosl; 43H: phoric acid ester chloride is obtained by adding to the X thiamine phosphoric acid ester chloride the equimolecular 5 wherein X is an anion selected from the group consisting of 2- 'furan carboxylic acid, 2,5-furan dicarboxylic acid, and a pharmaceutically acceptable inorganic and organic acid;

Y is an acid selected from the group consisting of 2- furan carboxylic acid, 2,5-furan dicarboxylic acid, and a pharmaceutically acceptable inorganic and organic acid;

R is a member selected from the group consisting of hydrogen and an ester-forming phosphoric acid, pyrophosphoric acid, and triphosphoric acid radical, whereby at least one of said members X and Y is derived from said furan carboxylic acids and whereby X is derived from said furan carboxylic acids while -NI-I .Y is a free amino group.

2. The thiamine compound according to claim 1,

wherein R is hydrogen,

NH .Y is the free amino group, and

X is the 2-furan car-boxylic acid anion.

3. The thiamine compound according to claim 1,

wherein R is hydrogen,

-NH .Y is the free amino group, and

X- is the 2,5-furan dicarboxylic acid anion.

4. The thiamine compound according to claim 1,

wherein R is the phosphoric acid radical of the formula flan -NH .Y is the free amino group, and X is the 2-furan carboxylic acid anion. 5. The thiamine compound according to claim 1, wherein R is the phosphoric acid radical of the formula i-0H --NH .Y is the free amino group, and X- is the 2,5-furan dicarboxylic acid anion. 6. The thiamine compound according to claim 1, wherein R is the triphosphoric acid radical of the formula NH .Y is the free amino group, and

X- is the 2-furan carboxylic acid anion.

7. The thiamine compound according to claim 1, wherein R is the triphosphoric acid radical of the formula OH OH OH (tit -NH .Y is the free amino group, and

X is the 2,5-furan dicarboxylic acid anion.

8. The thiamine compound according to claim 1, wherein R is the pyrophosphoric acid radical of the formula NH .Y is the free amino group, and

X is the Z furan carboxylic acid anion.

9. The thiamine compound according to claim 1, wherein a R is the pyrophosphoric acid radical of the formula NH .Y is the free amino group, and X- is the 2,5-furan dicarboxylic acid anion.

References Cited FOREIGN PATENTS 653,060 11/ 1962 Canada. 881,688 2/1943 France. 1,208,305 1/ 1966 Germany.

OTHER REFERENCES Okumura et al., J. Vitaminology, vol. 2 (1950), pp. 276-82.

ALEX MAZEL, Primary Examiner. R. J. GALLAGHER, Assistant Examiner.

U.S. Cl. XR 

